Prostaglandin E2 (PGE2) is one of the most broadly distributed prostanoids throughout animal species and widely produced within the body by the actions of cyclooxygenases (COX) on arachidonic acid. PGE2 is involved in a number of physiological and pathophysiological responses such as fever, pain, inflammation (non-patent document 1) and elicits its biological functions through four receptor subtypes EP1-4, all G-protein-coupled receptor.
Emerging biology has revealed important roles of EP4 receptors in immune system (non-patent documents 2 and 3). For example, EP4 receptor activation stimulates dendritic cells and promotes IL-23 production synergistically with CD40 and Toll-like receptor signaling. PGE2 then enhances the expansion of Th17 cells with IL-23. EP4 receptor activation promotes the differentiation of Th1 from naive T cells synergistically with IL-12. PGE2 synergistically induces IL-6 and IL-13 expression with LPS via EP4 receptors in macrophages. Th1, Th17 and macrophage cells play key roles in the development of autoimmune/inflammatory diseases. Thus, a selective EP4 receptor antagonist is expected to inhibit IL-23 & IL-6 production and suppression of Th1 & Th17 function (non-patent documents 4 and 5), reduce inflammatory pain and offers an attractive therapeutic approach for rheumatoid arthritis (RA), inflammatory bowel diseases and other autoimmune/inflammatory diseases.
Non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors are clinically proven to relieve inflammation and pain by inhibiting the synthesis of arachidonic acid pathway metabolites including PGE2. However, their use is associated with adverse effects due to pleiotropic function of arachidonic acid pathway metabolites and imbalance in their levels. An imbalance between TXA2 and PGI2, for example, has been implicated in the vasospasm, hyperaggregability and thromboembolism that are associated with many cardiovascular diseases (non-patent document 6). As EP4 selective antagonists specifically block PGE2 function through only EP4 receptor, leaving functions through other receptors intact, it is expected that they will not exhibit the adverse effects similar to that of NSAIDs and COX-2 inhibitors (non-patent document 7). Further, compared to other targeted therapies (e.g. JAK, TNFα, IL-6) for RA, EP4 antagonist has been shown to improve both joint damage and inflammatory pain in animal models. Thus, this mechanism has potential to “complete symptom management” for RA in clinic (non-patent document 8).
In addition to autoimmune diseases, endometriosis, aortic aneurysm (e.g. abdominal aortic aneurysm, thoracic aortic aneurysm, thoracoabdominal aortic aneurysm etc.) and ankylosing spondylitis are other indications for EP4 antagonist. Endometriosis (EM) is a chronic, estrogen-dependent inflammatory disease and defined as the presence of functional endometrial tissue at ectopic sites. It is a common disease that 10-20% of women of reproductive age are affected. The most common symptom is a dysmenorrhea. Chronic pelvic pain, dyspareunia, dyschezia (pain on defecation), loin pain, lower abdominal pain or back pain, pain on micturition, pain on exercise are also part of the symptoms of EM (non-patent document 9). Current treatments include surgical intervention, pharmacotherapies using NSAIDs, COX-2 inhibitors and hormonal therapies, or a combination of both. NSAIDs or COX-2 inhibitors are effective in relieving pelvic pain, but can cause severe side effects including gastrointestinal injury, nephropathy, and increase cardiovascular risk (non-patent document 10). Hormonal therapy controls disease conditions, but has side effect such as pseudomenopause and decreased bone density due to suppression of estrogen production (non-patent document 11). Development of a safer, but equally efficacious treatment is highly demanded. EP4 receptor proteins were abundantly expressed in human endometriosis tissues (ectopic and eutopic endometrium) during the proliferative phase of the menstrual cycle (non-patent document 12). In human immortalized endometriotic epithelial and stromal cells selective inhibition of EP4 induced apoptosis (non-patent document 12), inhibited proliferation (non-patent document 13), inhibited migration and invasion (non-patent document 14) and inhibited adhesion (non-patent document 15). These studies suggest that inhibition of EP4 signaling is a potential therapeutic option for women with EM (non-patent document 15).
Abdominal aortic aneurysm (AAA) is a common, progressive, and life-threatening degenerative vascular disease (non-patent documents 16 and 17). It is an inflammatory disorder characterized by localized connective tissue degeneration and smooth muscle cell apoptosis, leading to aortic dilatation and rupture (non-patent documents 18-20). After rupture occurs, the probability of mortality is greater than 60% (non-patent document 21). No pharmacotherapy has been found to be effective at decreasing the growth rate or rupture rate of AAAs except. In aneurysm walls, COX-2 is widely expressed in macrophages and smooth muscle cells, along with locally synthetized PGE2 (non-patent document 22). EP4 expression is increased in the aneurysm areas of human AAA tissues, both in human aortic aneurysm smooth muscle cell as well as in macrophages in the lesion (non-patent documents 23 and 24). EP4 receptor antagonist or global gene deletion of the EP4 receptor significantly decreased MMP-2 activation and IL-6 production in human AAA tissues and the rate of AAA formation in preclinical mouse models (non-patent document 23 and 25).
Ankylosing spondylitis is the prototypic spondyloarthropathy, one of a group of conditions which also includes psoriatic arthritis, reactive arthritis and arthritis complicating inflammatory bowel disease. Ankylosing spondylitis is highly heritable (non-patent documents 26 and 27) and familial (non-patent document 28). Men are affected 2-3 times more frequently than women. The disease is known to be strongly associated with HLA-B27. Since association between EP4 receptor gene (PTGER4) and ankylosing spondylitis has been also demonstrated (non-patent document 29), EP4 receptor is likely to be involved in disease pathogenesis. There is no cure for ankylosing spondylitis as yet, but the patient's back pain and stiffness usually show good symptomatic response to NSAIDs. Since EP4 antagonists are known to possess analgesic activity at least in animal models (non-patent documents 30 and 31), a safe and chronically-treatable EP4 antagonist may be an alternative symptom-relieving pharmacotherapy for ankylosing spondylitis.
Examples of the compound having a structure similar to the compound described in the present specification include the following compounds.
(1) Patent document 1 describes a compound represented by the formula:
wherein each symbol is as defined in the specification, which is useful as an agent for the prophylaxis or treatment of metabolic disease, cerebrovascular disease and the like.
(2) Patent document 2 describes a compound represented by the formula:
wherein each symbol is as defined in the specification, as a proton pump inhibitor (PPI), which is useful as an agent for the prophylaxis or treatment of peptic ulcer and the like.
(3) Patent document 3 describes a compound represented by the formula:
wherein each symbol is as defined in the specification, as a corticotropin releasing factor (CRF), which is useful as an agent for the prophylaxis or treatment of anxiety, depression, other psychiatric and neurological disorders, and the like.
(4) Patent document 4 describes a compound represented by the formula:
wherein each symbol is as defined in the specification, as a RAF kinase inhibitor, which is useful as an agent for the prophylaxis or treatment of cancer.
(5) Patent document 5 describes a compound represented by the formula:
wherein each symbol is as defined in the specification, as a mGluR1 antagonist, which is useful an agent for the prophylaxis or treatment of pain.